Naltrexol has been proposed as a treatment for heroin dependency. 6-β-Naltrexol is the major metabolite of naltrexone. We are interested in finding industrially applicable routes to 6α-naltrexol. Molecules of similar structure include α-noroxymorphol and α-nalbuphine.
The state of the art process for the production of such compounds involves the reduction of a 6-keto group on the corresponding naltrexone, noroxymorphone or 6-keto-nalbuphine using a borohydride, especially at low temperatures. This process is described in U.S. Pat. No. 5,756,745 (Mallinckrodt). Such borohydride reductions have been found to be difficult to scale up to commercial scale production, there are safety issues associated with storing and using borohydrides and the by-product boron salts need to be removed from the product.
WO2006/035195 (Johnson Matthey) describes the conversion of noroxymorphone to nalbuphine by a hydrogenation using platinum on carbon catalyst, followed by sodium borohydride addition.
WO2008/137672 (Mallinckrodt) aims to avoid the use of borohydride by the use of a ruthenium, rhodium or iridium asymmetric catalyst in combination with a hydrogen source and a solvent. The typical chiral catalysts are Noyori catalysts. Hydrogen sources include gaseous hydrogen at up to 100 atm or, preferably, a hydrogen transfer agent such as isopropanol or formic acid. If isopropanol is used, a small amount of activator such as KOH may be added, but the preferred hydrogen source is a 5:2 mixture of formic acid and triethylamine. Yields are stated to be 83% for nalbuphine, with a 99:1 6α-nalbuphine to 6β-nalbuphine ratio.
There remains a need for simple and inexpensive reduction method for this transformation.